Objective To explore the efficacy and safety of compound Kushen injection (CKI) combined with FOLFOX4 in the treatment of advanced colorectal cancer (CRC).Methods A total of 78 patients who were diagnosed with advanced CRC in our hospital between May 2015 and April 2018 and received chemotherapy were selected in this study. They were randomly divided into two groups. The control group received FOLFOX4 treatment, and the observation group received CKI combined with FOLFOX4 treatment. All patients underwent 4 cycles of treatment. Compare the treatment effects, the incidence of adverse reactions during chemotherapy, the changes in immune indicators and the 1-year survival rate between the two groups.Results After treatment, there was no significant difference in the effective rate between the two groups (P=0.062), but the disease progression rate was lower in the observation group than in the control group (P=0.028). The incidence rates of bone marrow suppression, gastrointestinal reactions and neurotoxic reactions were significantly lower in the observation group than in the control group (P=0.030, P=0.001, P=0.003). The immune function of patients in the control group declined significantly after treatment, while that in the observation group showed no changes. The 1-year progression-free survival rate of the observation group was higher than that of the control group (23.08% vs. 7.69%, P=0.017). In terms of overall survival, there was no significant difference between the two groups (P=0.290).Conclusion The CKI combined with FOLFOX4 has a good effect in the treatment of advanced CRC. It can reduce the incidence of adverse reactions, and help to protect the immune function of patients.